Administration of medicinal dry powders

ABSTRACT

A method of administering a metered dry powder combined dose of finely divided dry medication powders is disclosed, wherein said method comprises providing a relative motion between a nozzle of a dry powder inhaler and a dose bed carrying said combined dose of finely divided dry medication powder intended for delivery by the dry powder inhaler, the combined dose comprises metered quantities of at least two medicaments separately deposited on the dose bed, the relative motion causing the nozzle to pass over the combined dose for a simultaneous or sequential delivery of the medicaments during the course of a single suction of air.

TECHNICAL FIELD

The present invention relates to a method of administering medicamentsby an oral inhalation route to a user in need of doses comprising atleast two therapeutic medicinal dry powders, the doses being packaged tosuit a new method of aerosolizing a selected combined dose into air andmore particularly, the invention relates to a method of simultaneousdelivery in a single inhalation by a user of separate dry powderformulations of different medicaments constituting a combined dose.

BACKGROUND

Administration of drugs by an oral inhalation route is very much infocus today, because of advantages offered like rapid and predictableonset of action, cost effectiveness and high level of comfort for theuser. There are mainly two types of inhalers on the market, pressurizedmetered dose inhalers (pMDIs) comprising a suspension of fine medicamentparticles in a propellant gas and dry powder inhalers (DPIs) comprisingfine medicament particles as dry powder.

Dry powder inhalers (DPI) attract perhaps the most interest, compared topMDIs, because of the flexibility they offer in terms of nominal doserange i.e. the amount of active substance that can be administered in asingle inhalation. So far most development efforts have been directedtowards producing effective drugs and formulations for specific abnormalconditions and not so much towards developing the delivery device, i.e.the inhaler.

When inhaling a dose of dry medication powder it is important to obtainby mass a high fine particle fraction (FPF) of particles with anaerodynamic size preferably less than 5 μm in the inspiration air. Themajority of larger particles does not follow the stream of air into themany bifurcations of the airways, but get stuck in the throat and upperairways. It is not uncommon for prior art inhalers to have an efficacyof 10-20% only, i.e. only 10-20% of the metered dose by mass is actuallydelivered as particles with an aerodynamic size less than 5 μm. Sincemost drugs have undesirable side effects and some may be quite toxic ifoverdosed, it is important to keep the dosing to the user as exact aspossible and to design the delivery system, e.g. an inhaler, such thatthe efficacy becomes much higher than 10-20%, thereby reducing therequired amount of drug in the dose. Also, depending on the targetedsite of action, be it systemic or local in the throat and airways, it isdesirable to tailor the physical formulation of a medication powder insuch a way that it results in an advantageous particle aerodynamic sizedistribution by mass in the metered dose.

An interesting field of research concerns the possibility ofsimultaneous administration of combinations of different medicaments. Ofcourse, it is well known in prior art that a successful treatment of amedical condition may is require administration of more than one activesubstance, e.g. a medicament for relaxing the immediate symptoms likepain or bronchoconstriction and another medicament for treating theunderlying abnormal condition like systemic chemical imbalance or airwayinflammation respectively. However, it is often difficult to mix themedicaments into a metered dose, because the medicaments may be known tobe incompatible or else it is perhaps unknown if and how they interactbefore they are actually delivered to a subject Therefore, medicamentsare generally administered separately, in sequence or by separateroutes.

In the past decade research into respiratory diseases, their prophylaxisand treatment, has shown conclusively that simultaneous administrationof combinations of different medicaments may improve the clinicalcondition of patients considerably. In Switzerland patients diagnosedwith asthma have been prescribed FORADIL (formoterol, a bronchodilatingsubstance) together with PULMICORT (budesonide, an anti-inflammatorysteroid) since the 1980's for treatment of their asthma. Until recently,however, different asthma medicaments have generally been administeredseparately, in sequence or by separate routes, not in compositionscomprising more than one active ingredient. However, there are severalpublished patent applications and approved patents teaching methods oftreating respiratory disorders like asthma and chronic obstructivepulmonary disease (COPD) and pharmacologic compositions of differentbiologic and chemical substances for this purpose, where thecombinations offer overall advantages in the treatment of theseconditions. See for instance EP 0416950B1 “Medicaments”, EP 0416951B1“Medicaments comprising salmeterol and fluticasone”, EP 0613371B1 “Newcombination of formoterol and budesonid”, WO 98/15280 “New combination”,WO 00/48587 “Combinations of formoterol and fluticasone propionate forasthma”, WO 01/70198A1 “Stabilized dry powder formulations”, WO01/78737A1 “Medical combinations comprising formoterol and budesonid”,WO 01/78745A1 “Medical combinations comprising formoterol andfluticasone propionate”, WO 02/28368A1 “New combination for thetreatment of asthma”, WO 03/013547A1 “Pharmaceutical compositioncomprising salmeterol and budesonid for the treatment of respiratorydisorders”. However, the quoted documents deal with aspects offormulating, processing, stabilizing and using mixtures of at least twoingredients. The chemical compositions and mixing ratios between activeingredients are generally focused upon, not methods of administration ofsuch compositions or devices for that purpose. It is, however, difficultto mix dry medicament powders and optional excipients in a certainproportion consistently. The proportions in such a metered combined dosecannot be easily controlled, because the ratio of medicaments in anindividual, combined dose depends significantly on the particle forcesexisting in each medicament powder, between particles of differentmedicaments and between medicament powders and dose packaging materials.Hence, actual variations in the ratio between active ingredients fromcombined dose to combined dose may be too large, causing seriousproblems if a potent ingredient is delivered in a higher or lower amountthan expected.

Thus, there is room for improvements regarding methods and devices forsimultaneous administration of different medicaments, which combineadvantageously in treatment of certain medical disorders.

SUMMARY

A method of administering metered dry powder combined doses of finelydivided dry medication powders is disclosed. A metered dry powdermedicinal combined dose comprising at least two medicaments of separatedry powder formulations is prepared, whereby a metered powder quantityper medicament is deposited in a dose forming step, where the sum of thedepositions constitute the metered quantity of powder in the medicinalcombined dose. The deposits of the at least two medicaments are suitablykept separated from each other, such that the medicaments cannotdetrimentally interact after forming of the combined dose, and themedicinal combined dose can be introduced into an inhaler device for adelivery of the medicinal combined dose during the course of a singleinhalation, whereby the delivered medicinal combined dose is composed toa high degree by mass of de-aggregated fine particles of each of the atleast two medicaments.

Furthermore a therapeutic metered medicinal, combined dosage of finelydivided dry medication powders is disclosed wherein the therapeutic,metered combined dosage comprises metered quantities of at least twomedicaments, separately deposited; and the medicinal combined dosage isadapted for a user initiated delivery of the combined dosage during thecourse of a single inhalation through an inhaler device. The at leasttwo medicaments of the medicinal combined dosage are aerosolizedgenerally simultaneously or generally sequentially during an inhalation,depending on how the dosage is physically composed, whereby a delivereddosage to a user consists of a high degree by mass of fine particles ofeach medicament such that a large proportion of each medicament settlesin the intended target area in the airways and lungs of the user.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention, together with further objects and advantages thereof, maybest be understood by referring to the following detailed descriptiontaken together with the accompanying drawings, in which:

FIG. 1 illustrates in top and side views a first embodiment of combineddoses comprising two medicament deposits in separate compartments onto adose bed;

FIG. 2 illustrates in top and side views a second embodiment of combineddoses comprising three medicament deposits in separate compartments ontoa dose bed;

FIG. 3 illustrates in top and side views a third embodiment of combineddoses comprising two parallel medicament deposits onto a dose bed;

FIG. 4 illustrates in top and side views a fourth embodiment of combineddoses comprising several medicament deposits and separating excipientdeposits onto a dose bed;

FIG. 5 illustrates in top and side views a fifth embodiment of combineddoses comprising four medicament deposits and separating excipientdeposits onto a dose bed;

FIG. 6 illustrates in top and side views a sixth embodiment of combineddoses comprising two parallel medicament deposits on top of one anotheronto a dose bed;

FIG. 7 illustrates in top and side views a seventh embodiment ofcombined doses comprising two medicament deposits on top of one anotheronto a dose bed, but separated by a deposit of an excipient;

FIG. 8 illustrates in top and side views another embodiment of acombined dose comprising two medicaments separately deposited onto adose bed;

FIG. 9 illustrates in top and side views yet another embodiment of acombined dose comprising two medicaments separately deposited onto adose bed, but with some degree of overlap;

FIG. 10 a illustrates in a sectional view an example of a combined dosecomprising two medicament deposits on top of one another but separatedby a deposit of an excipient onto a dose bed and adjacent to tiecombined dose a nozzle in a starting position before the combined doseis released; and

FIG. 10 b illustrates in a sectional view an example of a combined dosecomprising two medicament deposits on top of one another but separatedby a deposit of an excipient onto a dose bed and adjacent to thecombined dose a nozzle in a relative motion sucking up the powderparticles to be dispersed into the air stream.

DETAILED DESCRIPTION

The present invention is based on a new method of forming combined dosescomprising more than one medicament deposited onto a dose bed and a newmethod of delivering such combined doses by an inhalation route to auser of a dry powder inhaler (DPI).

In the context of this application the word “medicament” is defined as apharmacological substance, which comprises at least one chemically orbiologically active agent. Further, a medicament may exist in a pureform of one or more pure active agents, or a medicament may be acompound comprising one or more active agents, optionally formulatedtogether with other substances, e.g. enhancers, carriers, diluents orexcipients. From this point on, the term “excipient” is used to describeany chemical or biologic substance mixed in with a pure active agent forwhatever purpose. In this document, only medicaments in dry powder formare discussed.

A “dose bed” is henceforth defined as a member capable of harboring ametered dose of one or more dry powders, where the dose is intended fora delivery to a user of a DPI in a single inhalation performed by theuser. In the present invention a combined dose comprises metereddeposits of at least two medicaments. The dose bed may be divided inseveral areas or incorporate two or more compartments intended fordeposits of dry powders. In a preferred embodiment the combined dose ispackaged for a continuous, prolonged delivery, i.e. the delivery periodis in a range 0.01 to 6 s, usually in a range 0.1 to 2 seconds, deliverytaking place sometime during the course of an inhalation as controlledby a purposefully designed DPI. Advantageously, such a DPI adopts anAir-razor method of gradual aerosolization of the combined dosecomprising introduction of a relative motion between an air-suckingnozzle and the powder dose. Advantages of a prolonged delivery of a dosefor inhalation are disclosed in our U.S. Pat. No. 6,571,793 (WO 02/24264A1), which is hereby incorporated in this document in its entirety as areference.

A preferred embodiment of a metered combined dose uses a dose bed splitup in at least two separate compartments, where each compartment isintended for a metered deposition of a particular medicament. Eachcompartment containing a metered amount of a specified medicament powdermay then be sealed, e.g. by foiling, such that the different medicamentsin the different compartments of the dose bed cannot interact in any wayand can not be contaminated by foreign substances or moisture.Alternatively, a common foil encloses all compartments, but sealingbetween compartments may be excluded if individual sealing is not arequirement. A dose carrier is normally engaged to carry at least onedose bed loaded with a dose, whereby the dose carrier may be insertedinto a DPI for administering a combined dose or doses sequentially to auser in need of treatment. A suitable carrier of doses is disclosed inour Swedish patent publication SE 0517 806 C2 (WO01/34233 A1), which ishereby incorporated in this document in its entirety as a reference.However, a dose bed may be designed to act as a carrier, intended fordirect insertion into a DPI. A suitable DPI for a continuous dosedelivery is disclosed in our U.S. Pat. No. 6,422,236 B1, which is herebyincorporated in this document in its entirety as a reference.

If complete physical separation of the deposits of the differentmedicaments making up the combined dose is not required, but some degreeof overlap or mixing is acceptable from a physical, chemical and medicalpoint of view, then other methods of separating the deposits may beimplemented. Depending on what degree of mixing is permitted differentways of separating deposits must be adopted. For example, in oneembodiment, the different medicaments may be deposited in parallelstrings onto the dose bed. The dose bed may use separate indentationswhere the powder should be deposited, but flat target areas for depositsin a single plane on the dose bed are equally possible. In anotherembodiment the different medicaments are deposited sequentially dot-wiseor string-wise onto different target areas of the dose bed. Yet anotherway of depositing the medicaments would be on top of one another, inlayer by layer, such that each medicament is deposited on top of thepreviously deposited one. If necessary, to stop chemical or biologicalinteraction or decomposition caused by, for example, adjacent medicamentpowders being incompatible, an isolating layer of a biologicallyacceptable, inert substance like carbohydrates, e.g. glucose or lactose,may be deposited between adjacent layers of medicament. A similar methodof separation may also be used to positively separate adjacent dots orstrings of medicaments, by depositing an inert substance betweenadjacent dots or strings of different medicament deposits onto the dosebed. When the combined dose has been completely formed it is usuallysealed from ingress of dirt and moisture by a foil covering the entiredose bed. A method of depositing microgram and milligram quantities ofdry powders using electric field technology is disclosed in our U.S.patent application Ser. No. 2003/0012865 A1, which is herebyincorporated in this document in its entirety as a reference.

Forming a combined dose comprising at least two medicaments in separatedry powder formulations may be done in different ways, known in priorart. The invention discloses that the components of the combined dose,i.e. the at least two medicaments need not be mixed or processedtogether prior to dose forming and, indeed, should normally be keptseparated during dose forming as well as after the combined dose isformed and sealed. The medicaments of the combined dose are thus keptseparated on the dose bed by a suitable method, as described in theforegoing, until the combined dose is about to be delivered by aninhalation route to a user.

Methods of dose forming include conventional mass or volumetric meteringand devices and machine equipment well known to the pharmaceuticalindustry for filling blister packs, for example. See European Patent No.EP 0 319 131 B1 and U.S. Pat. No. 5,187,921 for examples of prior art involumetric and/or mass methods and devices for producing doses ofmedicaments in powder form. Electrostatic forming methods may also beused, for example as disclosed in U.S. Pat. No. 6,007,630 and U.S. Pat.No. 5,699,649. Any method capable of producing metered micro- andmilligram quantities of dry powder medicaments may be used, evencompletely different methods may be applied to suit the differentmedicaments selected to be part of the combined doses to be produced.Total mass in a combined dose according to the present invention istypically in a range from 50 μg to 50 mg. Regardless of which formingand filling method is being used for a particular medicament, it isimportant during dose forming to make sure that intended medicaments areindividually metered and deposited onto their respective target areas orcompartments of the dose bed. The target areas or compartments of thedose bed, which combine to hold a dose, may be of same or differingsizes. The shape of compartments is governed by physical constraintsdefined by the type of dose bed used. As an example, a preferred type ofdose bed is an elongated strip of a biologically acceptable, inertmaterial, e.g. plastic or metal, between 5 and 50 mm long and between 2and 10 mm wide. The strip is further divided in separate target areas orcompartments arranged along the length of the elongated strip. The dosebed or, if necessary each compartment, receives an individual seal, forinstance in the form of a foil, in a step immediately subsequent to thedose forming.

An advantage of the present invention is that a potentially interestingmedicament may be individually selected on merits of its own forinclusion in a combined dose, in disregard of whether or not it ischemically or biologically compatible with other potentially interestingmedicaments. The combined dose may be designed to include medicaments,which have proven medical effects of different, desirable kinds, eventhough the selected medicaments may be chemically or biologicallyincompatible or unstable in the form of a mixture. Thus, the regulatoryprocess before introducing combined doses of medicament combinations onthe market may be drastically simplified. Yet another advantage of theinvention is the possibility of using pure, more or less potentmedication substances as selected medicaments of the combined dose,without included excipients. Non-exclusive, illustrative examples notlimiting the scope of the invention of suitable typical medicaments fortreatment of asthma and COPD to be combined in single combined doses inaccordance with the present invention are listed below:

-   Formoterol and Budesonide-   Formoterol and Ipratropium-   Formoterol and Fluticasone-   Formoterol and Tiotropium-   Ipratropium and Budesonide-   Ipratropium and Salbutamol

Illustrative examples, not limiting the scope of the invention andanalogous with respiratory medicaments of suitable medicaments for paincontrol, which may be advantageously combined to be combined in singlecombined doses according to the present invention, includenon-exclusively:

-   Almotriptan-   Analgesics-   Anticonvulsants-   Antidepressants-   Antiemetics-   Aspirin (lysine acetylsalicylic acid)-   Betablockers-   Calcium channel antagonists-   Codeine-   DHE-   Domperidone-   Eletriptan-   Ergotamine-   Frovatriptan-   Metoclopramide-   Naratriptan-   Isometheptene-   Opiates-   Paracetamol-   Rizatriptan-   Serotonin-   Sumatriptan-   Triptans-   Zolmitriptan

Optimal dosages of the respective active substances for prevention ortreatment of disorders may be determined by those skilled in the art,and will vary with the type of disorder, selected compounds and theirrespective potency, and the advancement of the disease condition.Furthermore, factors associated with the individual undergoing treatmentdetermine correct dosages, such as age, weight, sex etc. Depending onwhat are correct dosages, the correct deposits by mass for the preparedmedicaments may be calculated, such that metered deposits of eachmedicament to be included in the metered combined dose may be producedin a dose-forming step. In calculating a correct nominal deposit of massfor each medicament component the fine particle fraction, i.e. particleshaving a mass median aerodynamic diameter (MMAD) less than 5 μm, percomponent of the actual delivered dose must be taken into consideration.As discussed in the foregoing, the efficacy of inhalers differsconsiderably and it is thus important to include the expected efficacyof the chosen inhaler in the calculation of what is a suitable nominalmass deposit. Another parameter to consider when forming the combineddose is the physical formulation of included medication powders.Formulation objectives may differ for the different medicamentcomponents of the combined dose. The particle aerodynamic sizedistribution by mass may be targeted differently for the different dosecomponents in order to optimize the efficacy of each component in thetreatment of a particular disease in a host user. For instance, the MMADfor a steroidal medicament component should be larger than that of abronchodilating medicament component. Whereas maximum penetration intothe lungs is required of a bronchodilator, a minimum of systemicabsorbance and maximum local deposition in the targeted area of theairways is required of the steroid.

Compared to prior art, more opportunities are opened up by the presentinvention in selecting medicaments based on existing compositions withproven medical effects, rather than first developing a mixture orformulation of different medicaments and then proving that the newcombination is effective, stable and lacks serious side effects. Thepresent invention makes it possible to define combined doses using anycombination of pure medicaments, i.e. pure pharmacologic agents, andmedicaments comprising excipients. A combined dose thus formed onto adose bed may be introduced into a dry powder inhaler (DPI) such that themedicament components making up the combined dose may be aerosolized anddelivered in the inspiration air during the course of an inhalationthrough the DPI by a user.

The invention also offers interesting opportunities for combinations ofnew medicaments and combinations of new medicaments with existing,proven ones. Keeping the different medicaments separated according tothe invention may reduce the investment in time and resource necessaryfor getting the combined medicaments approved by the relevant regulatorybodies and released to the respective markets. For instance, no addedsubstance to stabilize the combined product will be needed and notesting to prove that the added substance is harmless needs beperformed. New areas of therapy are thus now suitable for treatment byinhalation. Besides asthma, COPD and pain, other examples not limitingthe scope of the invention, of medical areas of therapy, wherecombinations of medicaments administered in single combined doses by aninhalation route may improve the quality of treatment, lower the costsand make life for patients more comfortable, are non-exclusively:

-   Disorders of the alimentary tract or the digestive system-   Disorders of the cardiovascular system-   Disorders of the endocrine system-   Disorders of the respiratory system-   Genital or sexual disorders-   Disorders of the muscular or neuromuscular system-   Disorders of the-   Psychosomatic disorders-   Anti-infectives-   Allergic disorders-   Protective or antinoxious agents

The present invention differs from prior art inhalers and related dosedelivery methods by providing a combined dose comprising two or moreseparate medicaments, more or less separately deposited onto a dose bed.The combined dose is therefore not a composition of medicamentsconstituting a single physical entity, but rather two or more physicalentities contained in a single dose. Inserted into a DPI, the combineddose will be aerosolized such that the entities of the dose, i.e themedicaments, are delivered mostly sequentially or optionally mostlysimultaneously into the inspiration air during an inhalation by a user.Whether medicaments included in a combined dose are aerosolized mainlysequentially or mainly simultaneously depends partly on the physicalform of the combined dose, i.e. how the medicament deposits areinterrelated and partly on what type of inhaler is used to administerthe combined dose. It is obvious that an inhaler, which subjects all ofthe combined dose to a jet-stream of air will aerosolize the includeddeposits simultaneously and more or less mixed, whereas an inhalersubjecting the combined dose to a jet stream gradually, like a movingtornado, thereby not attacking all of the combined dose at once, nayaerosolize the deposits of the dose gradually over time. An object ofthe invention is to offer better control of combined dose release and tofacilitate a prolonging of the dose delivery in order to produce a highfine particle fraction (FPF) in the delivered, combined dose. Anotherobject of the invention is to achieve a high ratio of delivered,combined dose relative metered combined dose. Although it is possible tosuccessfully apply the invention to prior art inhalers, these tend todeliver the dose in too short a time, resulting in a poor FPF figure andlow efficacy. On the other hand, a gradual dose delivery is possibleusing a new inhaler design where a relative movement is introducedbetween the dose and a suction nozzle through which the inspirationairflow is channeled. This arrangement utilizes the inhalation effort ofthe user to aerosolize the combined dose gradually for a prolongedperiod, thus using the power of the suction more efficiently andeliminating in most cases a need for external power to aerosolize thecombined dose.

A powder Air-razor method is advantageously used for aerosolizing themedicament powders in the combined dose, the Air-razor providingde-aggregation and dispersal into air of the finely divided medicationpowders. Utilizing an effort of sucking air through a mouthpiece of aninhaler, said mouthpiece connected to a nozzle, the particles of thedeposited medicament powders, made available to the nozzle, aregradually de-aggregated and dispersed into a stream of air entering thenozzle. The gradual de-aggregation and dispersal is produced by the highshearing forces of the streaming air and a relative motion introducedbetween the nozzle and the powders of the combined dose. In a preferredembodiment, the medicament powders are deposited onto a dose bed, suchthat the powder deposits occupy a larger area than the area of thenozzle inlet. The nozzle is preferably positioned outside the depositedarea, not accessing the powder by the relative motion until the airstream into the nozzle, created by the suction, has passed a thresholdflow velocity. Coincidental with the application of the suction orshortly afterwards the relative motion will begin such that the nozzletraverses the powder dose gradually. The high velocity air going intothe nozzle inlet provides plenty of shearing stress and inertia energyas the flowing air hits the leading point of the border of the contourof the first medicament deposit. This powder Air-razor method, createdby the shearing stress and inertia of the air stream, is so powerfulthat the particles in the particle aggregates in the powder adjacent tothe inlet of the moving nozzle are released, de-aggregated to a veryhigh degree as well as dispersed and subsequently entrained in thecreated air stream going through the nozzle. If the medicament depositshave been made in separate compartments of the dose bed and individuallysealed, then obviously the compartments must be opened up first so thatthe nozzle can access the deposited powder in each compartment whensuction is applied. Naturally, this is also true if the deposits share acommon seal without an individual seal for each deposit. An arrangementfor this purpose is disclosed in our Swedish patent publication SE 517227 C2 (WO 02/24266 A1), which is hereby incorporated in this documentin its entirety as a reference. Depending on how the deposits are laidout on the dose bed, the nozzle will either suck up the depositssequentially or in parallel or in some serial/parallel combination.

Thus, the quality of combined dose delivery is dramatically improvedcompared to prior art performance, and leading to important advances indelivering a majority of fine particles of the medicaments of thecombined dose to the intended target area or areas in the user's airwaysand lungs with very little loss of particles settling in the throat andupper airways. Administering medicament combinations according to thepresent invention has a very positive therapeutic effect from a medical,psychological and social point of view on a host in need of treatmentwith a combination of at least two medicaments.

DETAILED DESCRIPTIONS OF DRAWINGS

Referring to reference numbers 1-100 of the drawings wherein likenumbers indicate like elements throughout the several views of tendifferent embodiments of a combined dose comprising at least twodeposits of at least two medicaments onto a dose bed as illustrated inFIGS. 1-10 presented here as non-limiting examples.

FIG. 1 illustrates a combined dose 100 comprising two differentmedicament deposits, 1 and 2, in separate compartments 21 and 22 onto adose bed 20, which may be capsules or blisters or moldings in the dosebed. An individual seal 13 for each compartment guarantees that themedicaments cannot be contaminated by foreign matter or by one another.The illustrated deposits are intended for a sequential delivery takingplace during an inhalation.

FIG. 2 illustrates a combined dose 100 comprising three differentmedicament deposits, 1, 2 and 3 in separate compartments 21, 22 and 23similar to FIG. 1, but arranged underneath the dose bed 20. Besides adifferent arrangement of compartments on the dose bed 20 and therespective seals 13, the main difference between FIG. 1 and FIG. 2 isthat deposit 3 may consist of a different medicament from deposits 1 and2 is or it may consist of either the medicament of deposit 1 or 2. It isthus possible not only to administer more than one medicament, but alsoto compose combined doses of e.g. two medicaments with a very high ratioof mass between them. The illustrated deposits are intended for asequential delivery taking place during an inhalation.

FIG. 3 illustrates a combined dose 100 comprising two differentmedicament deposits, 1 and 2, laid out in parallel strips onto separatetarget areas 11 and 12 respectively onto the dose bed 20. A commonprotective foil 13 protects the medicaments of the combined dose frombeing contaminated by foreign matters. The illustrated deposits areintended for a fully simultaneous delivery of the two medicaments takingplace during an inhalation.

FIG. 4 illustrates a combined dose 100 comprising two differentmedicaments, 1 and 2, each comprising several deposits separated bydeposits of an inert excipient 3. The deposits are laid out in a stringof spots onto a target area 11 on a dose bed 20. The deposits share acommon seal 13. The combined dose is intended for a sequential deliveryof incorporated medicament spots, said delivery taking place during aninhalation. The excipient deposits help to minimize unintentional mixingof the medicaments. If some mixing of medicaments can be accepted, thenthe excipient may be left out altogether. Combined doses composed ofspot deposits may of course comprise more medicaments than two. The massratio between medicaments may be easily set by controlling the ratiobetween the number of spots per medicament in combination with the sizeof the respective spots in terms of deposited mass. Naturally the spotsneed not necessarily be circular in shape, they may take an elongated orelliptical form, depending on which type of dose forming method is used.

FIG. 5 illustrates a combined dose 100 comprising deposits of fourdifferent medicaments, 1, 2, 4 and 5, separated by deposits of an inertexcipient 3. The deposits are laid out in two parallel groups of twoin-line strips of medicament onto a common target area 11 on a dose bed20. The deposits share a common seal. The excipient deposits help tominimize unintentional interaction of the medicaments. The combined doseis intended for a combined parallel/simultaneous and sequential deliveryof incorporated medicament strips, said delivery taking place during aninhalation.

FIG. 6 illustrates a combined dose 100 comprising two differentmedicaments, 1 and 2, each comprising a strip of deposited powder,medicament 1 deposited onto a target area 11 of a dose bed 20 andmedicament 2 deposited on top of the deposit of medicament 1. Thismethod of dose forming is an alternative to the ones previouslydisclosed and may be used when a certain level of interaction of themedicaments can be tolerated.

FIG. 7 illustrates a combined dose 100 comprising two differentmedicaments, 1 and 2, and an excipient 3, each comprising a strip ofdeposited powder. Medicament 1 is deposited onto a target area 11 of adose bed 20 and excipient 3 is deposited onto medicament 2 to insulatemedicament 1 from a deposit of medicament 2 on top of the deposits ofmedicament 1 and excipient 3. This way of forming doses is notrestricted to include only two medicaments, but several medicaments maybe deposited on top of one another, if necessary with an insulatingdeposit of excipient between layers.

FIG. 8 illustrates a combined dose 100 comprising two differentmedicament deposits, 1 and 2, of somewhat irregular shapes butseparately laid out onto a common target area 11 of the dose bed 20. Theillustrated deposits are intended for a sequential delivery of the twomedicaments taking place during an inhalation.

FIG. 9 illustrates a combined dose 100 comprising two differentmedicament deposits, 1 and 2, of somewhat irregular shapes but generallyseparately laid out onto a common target area 11 of the dose bed 20. Theillustrated deposits overlap slightly, resulting in a arbitrary mixture9. The deposits are intended for a mostly sequential delivery of the twomedicaments taking place during an inhalation.

FIGS. 10 a and 10 b illustrate a delivery of a combined dose 100comprising two different medicaments, 1 and 2, and an excipient 3, eachcomprising a strip of powder sequentially deposited in three differentlayers. A nozzle 25 with an established flow of air 26 going into it isput in a relative motion, parallel to the dose bed 20, such that thenozzle passes over the combined dose beginning at the right side R andending at the left side L of the dose bed. This Air-razor method resultsin a simultaneous, gradual delivery of medicaments 1 and 2 together withthe excipient 3. The powders of the deposits are mixed into an aerosol27 by the air flowing into the nozzle leading to simultaneous deliveryof the two medicaments and the excipient. This Air-razor method may beapplied to all embodiments of the present invention and results in asimultaneous or sequential or a combined simultaneous/sequentialdelivery of all included medicaments and optional excipients.

1. A method of administering a metered dry powder combined dose offinely divided dry medication powders, comprising: providing a relativemotion between a nozzle of a dry powder inhaler and a dose bed carryingsaid combined dose of finely divided dry medication powder intended fordelivery by the dry powder inhaler, the combined dose comprises meteredquantities of at least two medicaments separately deposited on the dosebed, the relative motion causing the nozzle to pass over the combineddose for a simultaneous or sequential delivery of the medicaments duringthe course of a single suction of air.
 2. The method according to claim1, further comprising: introducing the dose bed into the dry powderinhaler.
 3. The method according to claim 1, further comprising:delivering the medicaments by the dry powder inhaler (DPI) during thecourse of a prolonged delivery taking place in 0.01 to 6 s.
 4. Themethod according to claim 1, wherein the at least two medicaments areselected from the following two medicament pairs: Formoterol andBudesonide; Formoterol and Ipratropium; Formoterol and Fluticasone;Formoterol and Tiotropium; Ipratropium and Budesonide; and Ipratropiumand Salbutamol.
 5. A dry powder inhaler comprising: a nozzle; a dosebed; a combined dose of finely divided dry powders intended for deliveryby the dry powder inhaler, the combined dose comprises meteredquantities of at least two substances, separately deposited on the dosebed; and an arrangement for providing a relative motion between thenozzle and the dose bed, such that the nozzle passes over the combineddose for a simultaneous or sequential delivery of the substances duringthe course of a single suction of air and the relative motion.
 6. Thedry powder inhaler according to claim 5, further comprising a mouthpiececonnected to the nozzle and adapted for receiving an applied air suckingeffort.
 7. The dry powder inhaler according to claim 5, wherein thenozzle is initially positioned outside an area of the dose bed ontowhich the substances are being deposited.
 8. The dry powder inhaleraccording to claim 5, wherein the arrangement is arranged for providingthe relative motion once an air stream induced in the nozzle exceeds athreshold flow velocity.
 9. The dry powder inhaler according claim 5,wherein the dose bed is sealed with at least one foil and the dry powderinhaler further comprises an arrangement for opening the seal allowingthe nozzle access to the dose bed.
 10. The dry powder inhaler accordingto claim 9, wherein the dose bed comprises at least two compartments,the at least two substances are deposited in separate compartments andeach compartment is provided with a separate seal to prevent interactionbetween separately deposited substances.
 11. The dry powder inhaleraccording to claim 5, wherein at least one of the at least twosubstances is composed of a pure, chemical or biologic agent.
 12. Thedry powder inhaler according to claim 5, wherein at least one of the atleast two substances is presented in form of a dry powder compoundconsisting of an effective amount of a pure, chemical or biologic agentmixed with suitable excipients.
 13. The dry powder inhaler according toclaim 5, wherein the dose bed is formed as a blister pack, where thedose bed is designed to accept separate deposits of the substancesmaking up the pre-metered combined dose.
 14. The dry powder inhaleraccording to claim 5, further comprising a biologically acceptable,inert substance deposited between the deposits of the at least twosubstances to prevent the at least two substances from detrimentallyinteract after forming of the combined dose.
 15. The dry powder inhaleraccording to claim 5, wherein the at least two medicaments are selectedfrom the following two medicament pairs: Formoterol and Budesonide;Formoterol and Ipratropium; Formoterol and Fluticasone; Formoterol andTiotropium; Ipratropium and Budesonide; and Ipratropium and Salbutamol.